Method For Extracting At Least One Compound From A Liquid Phase Comprising A Functionalized Ionic Liquid, And Microfluidic System For Implementing Said Method

ABSTRACT

(EN) The invention concerns a method for extracting at least one chemical or biological compound from a liquid phase comprising at least one functionalized ionic liquid, via a liquid extracting fluid (F) which is miscible with said ionic liquid(s), and a microfluidic system ( 10 ) for implementing said method. The inventive extraction method includes moving, on one surface ( 12 ) of a microfluidic system ( 19 ), at least one microdrop ( 14 ) of said liquid phase into an extraction solution ( 20 ) which comprises said extracting fluid and which is localized on said surface to obtain in output of said solution, under the effect of an electric field, an extract (E) moving away from said surface which is rich in extracting fluid and enriched in said or at least one of said compound(s), and a raffinate (R) moving on said surface which is rich in ionic liquid(s) and deleted in said or one of said compound(s).

The present invention relates to a process for extracting at least onechemical or biological compound from a liquid phase comprising at leastone functionalized ionic liquid, and to a microfluidic system for theimplementation of this process.

Room temperature ionic liquids (abbreviated to RTIL) are increasinglyused in organic synthesis because of their particularly advantageousproperties (cf. “Room Temperature Ionic liquids. Solvents for synthesisand catalysis”, T. Welton, Chemical Reviews, 1999, 2071-2083). This isbecause these are relatively nonvolatile solvents with a low vaporpressure which are compatible with the majority of known chemicalreagents, which are thermally stable, which are relatively nonflammableand which can be recycled.

In addition to these applications as reaction solvents, room temperatureionic fluids have numerous advantages for liquid-liquid and liquid-gasextraction. Just like supercritical fluids or fluorinated solvents,these ionic liquids are generally immiscible with volatile organicsolvents (abbreviated to VOS) and, because of their very high vaporpressures, they can be separated by direct distillation from thesolvents (cf. “Modern Separation techniques for the Efficient Workup inOrganic Synthesis”, C. C. Tzschucke et al., Angewandte Chemie, Engl.Int. Ed., 2002, 3964-4000).

It is known in the literature to use these ionic liquids as extractionfluids during the following separation operations:

-   -   ionic liquid/other solvent or aqueous phase two-phase extraction        (cf. “RT ionic liquids as novel media for clean liquid-liquid        extraction”, J. G. Huddleston et al., Chem. Commun., 1998,        1765-1766);    -   liquid/liquid microextraction using a drop of an ionic liquid        coupled to liquid chromatography (cf. “Ionic liquid-based        liquid-phase microextraction, a new sample enrichment procedure        for liquid chromatography”, J. Liu et al., J. Chromatograph. A,        2004, 1026, 143-147);    -   separations of gaseous, liquid, sulfur-comprising contaminants        in hydrocarbons (cf. documents of patent WO-A-2003/070667 and        WO-A-2003/040264);    -   separation of compounds exhibiting very similar boiling points        (cf. document of patent WO-A-2002/074718); and    -   extraction of heavy metals by complexing agents in ionic liquids        (cf. “First application of calixarenes as extractants in        room-temperature ionic liquids”, S. Kojiro, Chemistry Letters,        2004, 320-321).

It should be noted that all these separation operations are targeted atextracting a compound using an extraction fluid composed of an ionicliquid, that is to say and causing this compound to migrate, by materialtransfer, from the liquid phase to the ionic liquid.

Recently, interest has been taken in functionalized room temperatureionic liquids, also known as task-specific ionic liquids (abbreviated toTSIL in the continuation of the present description), which areparticularly well suited to homogeneous-phase supported synthesis.Reference may be made on this subject to the document of patentWO-A-2004/029004.

These functionalized ionic liquids combine the advantages of synthesesin the liquid phase and on a solid support, owing to the fact that theymake it possible:

-   -   in the liquid phase, to carry out a large number of reactions,        to rapidly optimize the operating conditions and to synthesize        products in large amounts, and    -   on a solid support, to rapidly purify by successively washing        the solid support in various solvents.

French patent application No. 04 07623, filed on 8 Jul. 2004 on behalfof the Applicant Company and of the Centre National de la RechercheScientifique, presents a microfluidic system comprising a microreactorwhich is composed of a drop comprising at least one functionalized ornonfunctionalized ionic liquid. This microreactor is without walls, theinterface of the ionic liquid(s) with the surrounding medium and withthe support on which the drop is deposited defining the limits of themicroreactor.

This patent application also relates to processes for implementingchemical or biochemical reactions and/or mixtures using thismicroreactor of drop type, and it mentions the extraction and/or thepurification of the product(s) resulting from the reaction carried outin the drop of ionic liquid.

One aim of the present invention is to provide a process for theextraction of at least one chemical or biological compound from theliquid phase comprising at least one functionalized ionic liquid, via aliquid extraction fluid immiscible with said ionic liquid(s), whichmakes it possible to carry out in particular unit operations:

-   -   (i) of purification of a microdrop comprising a mixture, on the        one hand, of molecules of at least one chemical or biological        compound supported by at least one functionalized ionic liquid        and, on the other hand, of an excess of this or these        compound(s) which have not reacted with these supported        molecules and/or of byproducts of the reaction of this ionic        liquid with this or these compound(s) for the extraction of this        excess of unreacted compounds and/or these byproducts; and    -   (ii) of cleavage of the support in a microdrop comprising        molecules of chemical or biological compounds supported by at        least one functionalized ionic liquid, for the extraction of        these compounds.

To this end, the extraction process according to the invention comprisesmoving, on a surface of a microfluidic system, at least one microdrop ofsaid liquid phase in an extraction bath which comprises said extractionfluid and which is located on said surface in order to obtain, at theoutlet of said bath, under the effect of an electric field, an extractmoving away from said surface which is based on said extraction fluidand which is enriched in said or at least one of said compound(s) and araffinate moving about on said surface which is based on said ionicliquid(s) and which is depleted in said or at least one of saidcompound(s).

According to another characteristic of the invention, said microdrop ismoved in said bath under the effect of said electric field, in such away that it moves about in contact with said surface.

According to another characteristic of the invention, said extractionfluid is circulated in said bath by forced convection and continuouslyin order for said raffinate obtained to be composed of said ionicliquid(s) (i.e., in order for the latter to be obtained in the purestate).

In the case (i) above, said extract obtained then comprises a mixture,on the one hand, of said extraction fluid and, on the other hand, ofsaid excess of said compound(s) which are not reacted and/or of saidreaction byproduct(s), and said raffinate comprises said supportedmolecules.

In the case (ii) above, said extract obtained then comprises, bycleavage of said support, a mixture of said extraction fluid and of saidcompounds separated from said functionalized ionic liquid, and saidraffinate comprises the latter.

The term “liquid phase comprising at least one functionalized ionicliquid” which constitutes said microdrop which can be used according tothe invention is understood to mean, in the present description, amixture:

-   -   of at least one chemical or biological compound, and    -   of a pure functionalized ionic liquid, of a mixture of pure        functionalized ionic liquids or also a mixture of one or more        functionalized ionic liquid(s) and of one or more        nonfunctionalized ionic liquid(s), optionally with one or more        solvent(s).

It should be noted that said or each compound can be bonded to said orto each functionalized ionic liquid or else can be free in the mixture.

The or each functionalized (i.e., task-specific) ionic liquid which canbe used in the microdrop according to the invention exists in the liquidform at ambient temperature and it can be represented by the formula A₁⁺X₁ ⁻, in which:

-   -   a) A₁ ⁺ represents a functional or nonfunctional cation or else        a mixture of cations in which either none of the cations is        functional or at least one of the cations is functional,    -   b) X₁ ⁻ is a functional or nonfunctional anion or a mixture of        anions in which either none of the anions is functional or at        least one of the anions is functional, provided that    -   c) the cation A₁ ⁺ and/or the anion X₁ ⁻ carry at least one        functional group capable of reacting with said chemical or        biological compound.

It should be noted that a functionalized ionic liquid A₁ ^(+X) ₁ ⁻(i.e., comprising at least one functional ion) can act partly asreaction medium and partly as soluble support or matrix, whereas anonfunctionalized ionic liquid A₁ ⁺X₁ ⁻ acts solely as inert reactionmedium or matrix with regard to the reactants and is capable ofdissolving them.

The expression “functional cation” denotes a molecular group which hasat least one chemical functional group, a portion of this moleculargroup carrying a positive charge. The expression “functional anion”denotes a molecular group which has at least one chemical functionalgroup, a portion of this molecular group carrying a negative charge. Theexpression “nonfunctional cation” denotes a molecular group without thechemical functional group, a portion of this molecular group carrying apositive charge. The expression “nonfunctional anion” denotes amolecular group without a chemical functional group, a portion of thismolecular group carrying a negative charge.

In the present invention, it is possible to use, as A₁ ⁺, a functionalcation or a mixture of cations, at least one of which is functional,and/or, as X₁ ⁻, a functional anion or a mixture of anions, at least oneof which is functional, said functional cations and functional anionscorresponding to a respectively cationic or anionic ionic entity bondedto at least one functional group F_(i), F_(i) varying from F₀ to F_(n)and n being an integer varying from 1 to 10.

The functional group F_(i) can be chosen in particular from thefollowing functional groups: hydroxyl, carboxyl, amide, sulfone, primaryamine, secondary amine, aldehyde, ketone, ethenyl, ethynyl, dienyl,ether, epoxide, phosphine (primary, secondary or tertiary), azide,imine, ketene, cumulene, heterocumulene, thiol, thioether, sulfoxide,phosphorus-comprising groups, heterocycles, sulfonic acid, silane,stannane or functional aryl and any functional group resulting from achemical, thermal or photochemical conversion or a conversion bymicrowave irradiation of the preceding functional groups.

Some functionalized ionic liquids, in particular those with largeanions, such as NTf₂ ⁻, PF₆ ⁻, BF₄ ⁻ or CF₃SO₃ ⁻, can be liquid atambient temperature or melt at low temperature, for example

is liquid at ambient temperature (Tf represents CF₃SO₂).

Advantageously, said or at least one of said functionalized ionicliquids which can be used according to the invention is chosen from thegroup consisting of an ammonium salt, an imidazolium salt, a phosphoniumsalt, an onium salt and a mixture of several of these salts.

Use may be made, for example, of a functionalized onium salt of formulaA₁ ⁺X₁ ⁻ as reaction support which comprises a functional cation and/ora functional anion corresponding to an ionic entity Y—, namelyrespectively a cationic entity Y⁺— or an anionic entity Y⁻—, optionallybonded via an arm L, in particular an alkyl group comprising from 1 to20 carbon atoms, to at least one functional group F_(i), F_(i) varyingfrom F₀ to F_(n) and n being an integer varying from 1 to 10, it beingpossible for the functional cation to be represented in the formY⁺-L-F_(i) and the functional anion in the form Y⁻(L)_(k)-F_(i), k beingequal to 0 or 1, and it being possible for the functional anion torepresent, when k is equal to 0, a simple anion, corresponding toY⁻F_(i), chosen in particular from:

OH⁻, F⁻, CN⁻, RO⁻, RS⁻, RSO₃ ⁻, RCO₂ ⁻ or RBF₃ ⁻, where R represents analkyl group comprising from 1 to 20 carbon atoms or an aryl groupcomprising from 6 to 30 carbon atoms.

The expression “functionalized onium salt” denotes the ammonium,phosphonium and sulfonium salts as well as all the salts resulting fromthe quaternization of an amine, of a phosphine, of a thioether or of aheterocycle comprising one or more of these heteroatoms, and carrying atleast one functional group F_(i). This expression also denotes an oniumsalt, the cation of which as defined above is not functionalized but theanion of which carries a functional group F_(i). This expression canalso denote a salt, the anion and the cation of which carry a functionalgroup F_(i). A preferred functionalized onium salt is chosen inparticular from the following:

m being an integer from 0 to 20.

Mention may be made, as examples of nonfunctionalized ionic liquidswhich can be used in the microdrops according to the invention incombination with one or more functionalized ionic liquids, of, forexample, onium salts chosen from imidazolium, pyridinium, Me₃N⁺-Bu orBu₃P⁺-Me cations and NTf₂ ⁻, PF₆ ⁻ or BF₄ ⁻ anions, such as1-butyl-3-methylimidazolium tetra-fluoroborate [bmim] [BF₄],1-butyl-3-methylimidazolium hexafluorophosphate [bmin] [PF₆],1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide [bmin][NTf₂], 1-ethyl-3-methylimidazolium hexafluoro-phosphate [emim] [PF₆]and butyltrimethylammonium bis(trifluoromethylsulfonyl)imide[btma][NTf₂].

According to another characteristic of the invention, said extractionfluid used in the extraction process according to the invention can beof organic or aqueous solvent type and it advantageously comprises atleast one volatile organic solvent (VOS) chosen from the groupconsisting of diethyl ether, ethyl acetate and chlorinated solvents,such as dichloromethane, chloroform or carbon tetrachloride.

In an alternative form, said extraction fluid can comprise at least oneaqueous solvent, such as water subjected to deionization.

According to another advantageous characteristic of the extractionprocess according to the invention, said electrically conductingmicrodrop is moved in contact with said surface under the effect of anelectric field, preferably by moving, by electrowetting (ElectroWettingon Dielectric (EWOD)), said microdrop both in said bath and upstream anddownstream of the latter, via a plurality of electrodes covering saidsurface.

These electrodes, supported by the substrate of the microfluidic system,are insulated and surface treated in order to obtain low wetting of saidmicrodrops bathing in said extraction fluid. It should be noted thatthese microdrops are electrically conducting, due to the or each ionicliquid which they comprise, whereas said extraction fluid exhibits avirtually zero electrical conductivity.

Advantageously, the extraction process according to the invention isimplemented by moving said microdrop continuously in said bath, whichmakes it possible to optimize material transfer by force diffusionbetween said microdrop to be purified and said extraction fluid.

More advantageously still, said microdrop is moved in said bath along apredetermined path and preferably around a central region of the bath,for example circularly, which makes it possible to effectively localizesaid bath on said surface of the microfluidic system.

According to a first embodiment of the invention, said bath and saidextract are respectively obtained by at least one stream for introducingsaid extraction fluid and by at least one stream for extracting saidbath, at least one of these introduction and extraction streams beingconveyed in a capillary which extends and emerges above said surface.

According to a first implementational example of this first embodimentaccording to the invention, said extraction bath is formed by a drop ofsaid extraction fluid which is deposited on said surface and which is incommunication with the entire surrounding space situated above saidsurface, and at least one of said introduction and extraction streamsmoves along inside a capillary under which said extraction drop isformed.

According to a second implementational example of this first embodimentaccording to the invention, said extraction bath is formed by a confinedvolume of said extraction fluid which is delimited by two respectivelylower and upper walls formed by said surface and by a sheet mounted onsaid surface, said volume being in communication substantially with theentire lateral surrounding space between said walls, and at least one ofsaid introduction and extraction streams moving along inside a capillaryemerging in an orifice of said sheet and being in communication withsaid confined volume.

According to a second embodiment of the invention, said bath and saidextract are respectively obtained by at least one stream for introducingsaid extraction fluid and by at least one stream for extracting saidbath, at least one of these introduction and extraction streamsextending into the body of said microfluidic system on emerging at saidsurface.

According to a first implementational example of this second embodimentaccording to the invention, said extraction bath is formed by a drop ofsaid extraction fluid which is deposited on said surface and which is incommunication with the entire surrounding space above said surface, andat least one of said introduction and extraction streams moving alonginside a channel embedded in said microfluidic system on which saidextraction drop is formed.

According to a second implementational example of this second embodimentaccording to the invention, said extraction bath is formed by a confinedvolume of said extraction fluid which is delimited by two respectivelylower and upper walls formed by said surface and by a sheet mounted onsaid surface, said volume being in communication substantially with theentire lateral surrounding space between said walls, and at least one ofsaid introduction and extraction streams moving along inside a channelembedded in said microfluidic system and which is flush with saidsurface.

In accordance with these first and second examples of the abovementionedfirst and second embodiments according to the invention:

-   -   said introduction and extraction streams advantageously emerge        in said bath substantially perpendicular to said surface,    -   said extraction stream is advantageously recycled continuously        in said introduction stream, this “regeneration” of the        extraction fluid making it possible to reduce the amount thereof        used, and    -   said extraction bath (i.e., said extraction drop or said        confined volume) is open to the surrounding space on at least        two of its opposite sides, for moving, in contact with said        surface, said microdrop upstream and downstream of said bath.

In accordance with the first example relating to the abovementionedfirst or second embodiments according to the invention, said extractiondrop is removed from said surface by suction in order to obtain saidextract.

Preferably, the microdrop composed of said liquid phase which issubjected to extraction according to the invention exhibits a volume ofbetween 0.1 μl and 10 μl, and the volume of this microdrop is planned tobe much less than that of the extraction bath in order to optimize thediffusion into the latter.

A microfluidic system according to the invention for the implementationof the extraction process as defined above is of the type exhibiting asubstrate, one surface of which is covered with electrodes suitable formoving thereon, under the effect of an electric field, microdrops of aliquid phase comprising at least one functionalized ionic liquid.

According to the invention, this microfluidic system is provided withmeans for introducing a liquid extraction fluid onto said surface andfor extracting it therefrom by forced convection, so as to obtain anextraction bath which is located on said surface for the extraction ofat least one chemical or biological compound from said liquid phase andwhich is open to the surrounding space on at least two of its oppositesides, for moving, in contact with said surface, said microdrop upstreamand downstream of said bath.

Mention may be made, as substrate which can be used in said analyticaldevice, of any inorganic or organic and biocompatible substrate.

In connection with the abovementioned first embodiment according to theinvention, this system is advantageously such that said means forintroducing and extracting said extraction fluid respectively comprisetwo capillaries, at least one of which extends and emerges above saidsurface and perpendicular to the latter.

In connection with the abovementioned second embodiment according to theinvention, this system is advantageously such that said means forintroducing and extracting said extraction fluid respectively comprisetwo channels, at least one of which is embedded in said microfluidicsystem and is flush with said surface perpendicular to the latter, so asto be in communication with said bath.

In connection with said first example of the first and secondembodiments according to the invention, said means for introducing andextracting said extraction fluid are appropriate for said extractionbath to be formed by a drop of said extraction fluid in communicationwith the entire surrounding space situated above said surface.

In connection with said first example of the second embodiment accordingto the invention, said channels are appropriate for said drop formingsaid bath to cover the respective ends of these channels.

In connection with said second example of the first and secondembodiments according to the invention, said microfluidic systemadditionally comprises a sheet which is mounted on said surface viavertical supports and which delimits, with said surface, tworespectively upper and lower walls defining a confined volume for saidbath, which is in communication substantially with the entire lateralsurrounding space between said walls. This sheet can optionally act ascounterelectrode in the electrowetting process.

In connection with said second example of said second embodimentaccording to the invention, said channels are flush with said surfacebetween vertical supports which connect the periphery of said sheet tosaid surface, so as to form said confined volume forming said bath.

According to another characteristic of the invention, said microfluidicsystem is advantageously such that:

-   -   the electrodes covering the substrate, such as gold electrodes,        are covered with an electrical insulator, such as silica or        silicon nitride (Si₃N₄) , and    -   said sheet is based on borosilicate glass and on a plastic, and        said supports are based on a photosensitive resin, such as an        epoxy resin, this sheet being deposited on these supports via an        adhesive.

The abovementioned characteristics of the present invention, and others,will be better understood on reading the following description ofseveral implementation examples of the invention, given by way ofillustration and without implied limitation, said description being madein connection with the appended drawings, among which:

FIG. 1 is a summarizing process diagram illustrating examples ofapplications of the extraction process according to the invention,

FIG. 2 is a diagrammatic perspective view of a microfluidic systemaccording to a first embodiment of the invention,

FIG. 3 is a diagrammatic perspective view of a microfluidic systemaccording to an alternative embodiment of FIG. 2,

FIG. 4 is a diagrammatic perspective view of a microfluidic systemaccording to a second embodiment of the invention,

FIG. 5 is a diagrammatic perspective view of a microfluidic systemaccording to an alternative embodiment of FIG. 4,

FIG. 6 diagrammatically illustrates various stages of a process for themanufacture of a substrate seen in cross section of a microfluidicsystem according to FIG. 2,

FIG. 7 diagrammatically illustrates a process for manufacture of acounterelectrode seen in cross section and intended to be assembled onthe substrate of FIG. 6, and

FIG. 8 is a diagrammatic cross sectional view of a microfluidic systemaccording to FIG. 2 obtained by assembling the counterelectrode of FIG.7 on the substrate of FIG. 6.

FIG. 1 illustrates a synthetic process employing the reaction A+B→A−B ona support comprising at least one functionalized ionic liquid “TSIL”, itbeing possible for this reaction to be of chemical type (creation ofcovalent bond) or of biological type (affinity of reaction, such ashybridization, antibody/antigen interaction or protein/substrateinteraction, without implied limitation).

Stage 1 of this process illustrates a first reaction between moleculesof this ionic liquid TSIL and molecules of a first reactant A, in orderto obtain a mixture 1 a comprising supported molecules TSIL-A, excessunreacted molecules of the reactant A and molecules A′ corresponding toa byproduct from this first reaction.

Stage 2 of this process illustrates a first unit operation forseparation of the unreacted reactant A and of the byproduct A′ by aliquid/liquid extraction according to the invention applied to thismixture 1 a via an extraction fluid F. An extract E comprising, inaddition to the extraction fluid F, molecules of A and of A′ and araffinate R comprising the supported molecules TSIL-A are thus obtained.

Stage 3 of this process illustrates a second reaction between thesesupported molecules TSIL-A of the raffinate R and molecules of a secondreactant B, in order to obtain a mixture 3 a comprising supportedmolecules TSIL-A−B, excess molecules of the reactant B which have notreacted with the supported molecules TSIL-A and molecules B′corresponding to a byproduct of this second reaction.

Stage 4 of this process illustrates a second unit operation forseparation of the unreacted reactant B and of the byproduct B′ byliquid/liquid extraction according to the invention applied to thismixture 3 a via an extraction fluid F. An extract E′ comprising, inaddition to the extraction fluid F, molecules of B and of B′ and araffinate R′ comprising the supported molecules TSIL-A−B are thusobtained.

Stage 5 of this process illustrates a third unit operation for “cleavageof the support” which consists in “cleaving” and in then separating, byliquid/liquid extraction according to the invention applied to thisraffinate R′ via an extraction fluid F, the molecules of TSIL support(raffinate R″ obtained) from the supported reaction product A−B (extractE″ obtained).

The microfluidic system 10 according to the invention was illustrated inFIG. 2 and comprises a substrate 11, one surface 12 of which is coveredwith electrodes 13 which are, for example, based on gold and which arecovered with an electrical insulator, such as silica or silicon nitride.These electrodes 13 are appropriate for making it possible to move, overthe surface 12, advantageously by electrowetting, microdrops 14 of aliquid phase comprising at least one functionalized ionic liquid (forexample, TSIL-A) and free substances in solution (A and A′), cf. FIG. 1.

This system 10 is provided with capillaries 15 and 16 which arerespectively intended to introduce a liquid extraction fluid F onto thesurface 12 and to extract it therefrom by force convection and whichboth extend and emerge above the surface 12 and perpendicular to thelatter, so as to obtain an extraction bath 20 based on the extractionfluid which is located on the surface 12 for the extraction of at leastone chemical or biological compound (A, A′, for example, cf. FIG. 1)from the liquid phase.

To this end, the system 10 comprises a sheet 17 in which the capillaries15 and 16 emerge via two respective orifices 18 of the sheet 17, so thatthese capillaries 15 and 16 are in communication with the bath 20. Thesheet 17 is provided at its periphery with vertical supports 19 mountedon the surface 12 and this sheet 17 delimits, with the surface 12, aconfined volume of parallelepipedal shape for this bath 20, after thefashion of an open “cover”. As illustrated in FIG. 2, this bath 20 is incommunication substantially with the entire lateral surrounding spacebetween the surface 12 and the sheet 17, in order to make it possible tomove, in contact with the electrodes 13, each microdrop 14 byelectrowetting in the bath 20 and upstream and downstream of the latter.

For example, in connection with the unit operation 2 of FIG. 1, thesystem 10 is appropriate for obtaining, by force diffusion of themicrodrop 14 in the bath 20 and continuous circulation of the extractionfluid F:

-   -   via the extraction capillary 16, an extract E comprising the        extraction fluid and the compounds A and A′, and    -   via electrodes 13, a microdrop of raffinate R comprising the        grafted ionic liquid TSIL-A in the pure state for the purpose of        another operation, e.g. another chemical or biological reaction        or an analysis.

For the following description of the other embodiments of the inventionrelating to FIGS. 3 to 5, use has to be made of the numerical referencesincreased by 100 to denote components of the corresponding microfluidicsystem which are identical or analogous to those of FIG. 2.

The microfluidic system 10 according to the invention which isillustrated in FIG. 3 differs from the system 10 of FIG. 2 solely inthat it is appropriate for forming an extraction bath 120 composed of adrop deposited on the surface 112 via the introduction capillary 115 andwithdrawn from the surface 112 by suction via the capillary 116, so thatthe extraction fluid F is in circulation via these capillaries 115 and116. The drop forming this extraction bath 120 is thus planned to beformed under the capillaries 115 and 116 and it is in communication withthe entire surrounding space situated above the surface 112.

For example, in connection with the unit operation 2 of FIG. 1, thesystem 110 is appropriate for obtaining, by force diffusion of themicrodrop 114 into the drop forming the bath 120 and continuouscirculation of the extraction fluid F:

-   -   via the capillary 116, an extract E comprising the extraction        fluid F and the compounds A and A′, and    -   via the electrodes 113, a microdrop of raffinate R which is        moved over the surface 112 and which comprises the grafted ionic        liquid TSIL-A in the pure state for the purpose of another        operation, e.g. a reaction or an analysis.

The microfluidic system 210 according to the invention, which isillustrated in FIG. 4, differs from the system 110 of FIG. 3 only inthat it is provided with two channels 215 and 216 embedded in thesubstrate 211 and which are flush with the surface 212 of this substrate211 perpendicular to the latter, in place of the capillaries 115 and116.

The introduction channel 215 is appropriate for receiving the extractionfluid F via its inlet 215 a emerging at a face perpendicular to thesurface 212 and, via a right-angled elbow 215 b which it comprises, fordelivering it in the form of a drop via its outlet 215 c which is flushwith the surface 212, so as to form the extraction bath 220 bycontinuously depositing and sucking off this drop. The extractionchannel 216 is appropriate for withdrawing from the bath 220, via theextraction fluid F, the extract E comprising, for example, the excessreactant A and the byproduct A′ via its inlet 216 a which is flush withthe surface 212, and, via a right-angled elbow 216 b which it comprises,for withdrawing it from the substrate 211 via an outlet 216 c emergingon another face of the substrate 211 perpendicular to the face 212.

For example, in connection with the unit operation 2 of FIG. 1, thesystem 210 is appropriate for obtaining, by force diffusion of themicrodrop 214 into the drop forming the bath 220 and continuouscirculation of the extraction fluid F:

-   -   via the capillary 216, an extract E comprising the extraction        fluid F and the compounds A and A′, and    -   via the electrodes 213, a microdrop of raffinate R which is        moved over the surface 212 and which comprises the grafted ionic        liquid TSIL-A in the pure state for the purpose of another        operation, e.g. a reaction or an analysis.

In a third embodiment, not represented, it can be advantageous toprovide a capillary for introducing fluid via the top and a capillaryfor extracting via the substrate, without a cover-forming sheet. Theadvantage of this combination is to combine the advantages of each ofthe two other embodiments:

-   -   simplified technology, due to the absence of cover;    -   no passage from an open environment to a confined environment,        due to the absence of cover;    -   perfect positioning of the extraction region over the        microfluidic system, by centering the introduction capillary        over this region;    -   possibility of completely withdrawing the extraction liquid via        the capillary provided in the substrate.

In these embodiments involving movements by electrowetting, it can beadvantageous to add a counterelectrode to the system, for example in theform of a conducting wire in contact with the microdrop.

In the same way, the microfluidic system 310 according to the inventionwhich is illustrated in FIG. 5 differs from the system 10 of FIG. 2 onlyin that it is provided with two channels 315 and 316 embedded in thesubstrate 311 which are analogous to the channels 215 and 216 of FIG. 4.

After the fashion of the channels 215 and 216 of FIG. 4, the channels315 and 316 are flush with the surface 312 of the substrate 311 betweenvertical supports 319 which connect the periphery of the sheet 317 tothe surface 312, so as to form a confined volume forming the extractionbath 320.

For example, in connection with the unit operation 2 of FIG. 1, thesystem 310 is appropriate for obtaining, by force diffusion of themicrodrop 314 into the bath 320 and continuous circulation of theextraction fluid F:

-   -   via the extraction capillary 316, an extract E comprising the        extraction fluid and the compounds A and A′, and    -   via the electrodes 313, a microdrop of raffinate R comprising        the grafted ionic liquid TSIL-A in the pure state for the        purpose of another operation, e.g. a reaction or an analysis.

It should be noted that the microfluidic systems 10 to 310 according tothe invention make it possible to separately recover the two liquidphases composed of the extract E and of the raffinate R. Thus, for the“purification” stages 2 and 4 of FIG. 1, the microdrop of TSIL-A orTSIL-A−B is recovered and the extraction fluid F comprising theimpurities A′ and B′ and the excess reactants A and B is removedseparately, whereas, for stage 5 of “cleavage of the support”, thereaction product A−B is recovered in the extraction fluid F and the TSILmicrodrop is recycled separately, for example for other reactions.

The liquid/liquid extraction process according to the invention isadvantageously employed in the following way.

The electrically conducting microdrops 14 to 314 based on functionalizedionic liquid(s) are moved by the electrowetting technique referred to asEWOD (ElectroWetting on Dielectric), voltages of 10 to 100 V beingapplied. To this end, the electrodes 13 to 313 are insulated and surfacetreated beforehand in order to obtain low wetting of the microdrops 14and 314 immersed in the extraction bath 20 to 320. In contrast to thesemicrodrops 14 to 314, the extraction fluid F chosen, such as a volatileorganic solvent (e.g., diethyl ether, ethyl acetate or a chlorinatedsolvent), exhibits a very low electrical conductivity, so that it is notmoved at the surface 12 to 312 of the microfluidic system 10 to 310.

The extraction according to the invention is carried out at ambienttemperature (i.e., typically between 20 and 25° C.) or optionally whileslightly cooling the microfluidic system 10 to 310, in order to limitthe evaporation of the extraction fluid F.

In order to optimize the material transfer by force diffusion betweenthe microdrop 14 to 314 and the extraction fluid F and the localizationof the extraction bath 20 to 320 on the surface 12 to 312, thismicrodrop is moved continuously in said bath around a central point ofthe latter.

FIGS. 6 to 8 illustrate, by way of example, the essential stages of aprocess for the manufacture of the microfluidic system 10 according tothe invention incorporating the sheet 17.

As illustrated in FIG. 6, the substrate 11 according to the invention isobtained essentially by carrying out the following stages:

-   -   in a first stage 30, a network of electrodes 13 is deposited by        photolithography in or on the substrate 11, which is, for        example, based on “Pyrex” glass or on oxidized silicon;    -   in a second stage 40, these electrodes 13 are electrically        insulated by a deposited layer 41 of silica or of Si₃N₄ produced        by PECVD (plasma enhanced chemical vapor deposition) and then        the deposited layer 41 obtained is subjected to photolithography        in order to release the contact; then    -   in a third stage 50, “partitions” 51 of photosensitive resin        “SU8” are deposited by photolithography on the substrate 11 thus        treated, which partitions are provided in order to perform a        role analogous to that of the supports 19 in FIG. 2, for the        purpose of the subsequent assembling of the counterelectrode 17        on the substrate 11.

As illustrated in FIG. 7, when a counterelectrode is desired on thesheet 17, it is obtained by depositing by photolithography, on a sheetmade of “Pyrex” glass or of plastic pierced with openings 18, a coating61 made of ITO (indium tin oxide) on the lower face of the sheet whichis intended to face the electrodes 13 of the substrate 11. Optionally,this layer of ITO can be covered with a layer of controlledhydrophobicity, in order to improve the moving of the drops.

As illustrated in FIG. 8, the counterelectrode 17 thus obtained isassembled on the “partitions” 51 of the substrate 11 by the “adhesivescreen printing” technique, a film of adhesive which is homogeneous 71being deposited at the interface between the coating 61 and these“partitions” 51. This film of adhesive 71 exhibits a thickness of lessthan a few micrometers and the adhesive used is, for example, sold bySupratec under the name “Delo-Katiobond 45952”. Reference may be made,for example, to the document of patent WO-A-00/77509 for a precisedescription of this “adhesive screen printing” technique.

1-34. (canceled)
 35. A process for extraction of at least one chemicalor biological compound from a liquid phase including at least onefunctionalized ionic liquid, via a liquid extraction fluid that isimmiscible with the ionic liquid, the process comprising: moving, on asurface of a microfluidic system, at least one microdrop of the liquidphase in an extraction bath that includes the extraction fluid and thatis located on the surface to obtain, at an outlet of the bath, undereffect of an electric field, an extract moving away from the surfacethat is based on the extraction fluid and that is enriched in the atleast one compound and a raffinate moving about on the surface that isbased on the ionic liquid and that is depleted in the at least onecompound.
 36. The process as claimed in claim 35, wherein the microdropis moved in the bath under the effect of the electric field such thatthe microdrop moves about therein in contact with the surface.
 37. Theprocess as claimed in claim 35, wherein the extraction fluid iscirculated in the bath by forced convection and continuously in orderfor the raffinate obtained to be composed of the ionic liquid.
 38. Theprocess as claimed in claim 36, wherein the microdrop is moved incontact with the surface by electrowetting in the bath and upstream anddownstream of the latter via a plurality of electrodes covering thesurface, the microdrop being electrically conducting, unlike theextraction fluid, the electrical conductivity of which is virtuallyzero.
 39. The process as claimed in claim 38, wherein the microdrop ismoved along a predetermined path around a central region of the bath.40. The process as claimed in claim 35, wherein the bath and the extractare respectively obtained by at least one stream for introducing theextraction fluid and by at least one stream for extracting the bath, atleast one of the introducing and extracting streams extending andemerging above the surface.
 41. The process as claimed in claim 35,wherein the bath and the extract are respectively obtained by at leastone stream for introducing the extraction fluid and by at least onestream for extracting the bath, at least one of the introducing andextracting streams extending into the microfluidic system on emerging atthe surface.
 42. The process as claimed in claim 40, wherein theintroducing and extracting streams emerge in the bath substantiallyperpendicular to the surface.
 43. The process as claimed in claim 40,wherein the extracting stream is recycled in the introducing stream. 44.The process as claimed in claim 35, wherein the extraction bath is opento a surrounding space on at least two of its opposite sides, formoving, in contact with the surface, the microdrop upstream anddownstream of the bath.
 45. The process as claimed in claim 44, whereinthe bath is deposited on the surface and an operation for removaltherefrom is carried out by suction to obtain the extract, such that thebath is in communication substantially with an entire surrounding spacesituated above the surface.
 46. The process as claimed in claim 44,wherein the extraction bath is formed by a drop of the extraction fluidthat is in communication with an entire surrounding space situated abovethe surface.
 47. The process as claimed in claim 40, wherein at leastone of the introducing and extracting streams moves along inside acapillary under which the drop of the extraction fluid is formed. 48.The process as claimed in claim 41, wherein at least one of theintroducing and extracting streams moves along inside a channel embeddedin the microfluidic system on which the drop of the extraction fluid isformed.
 49. The process as claimed in claim 44, wherein the extractionbath is formed by a confined volume of the extraction fluid that isdelimited by two respectively lower and upper walls formed by thesurface and by a sheet mounted on the surface, the volume being incommunication substantially with an entire lateral surrounding spacebetween the walls.
 50. The process as claimed in claim 40, wherein atleast one of the introducing and extracting streams moves along inside acapillary emerging in an orifice of the sheet.
 51. The process asclaimed in claim 41, wherein at least one of the introducing andextracting streams moves along inside a channel embedded in themicrofluidic system and that is flush with the surface.
 52. The processas claimed in claim 35, wherein the microdrop of the liquid phaseexhibits a volume of between 0.1 μl and 10 μl.
 53. The process asclaimed in claim 35, wherein the microdrop subjected to the extractioncomprises a mixture: of molecules of the chemical or biological compoundsupported by the functionalized ionic liquid, and of an excess of thechemical or biological compound that have not reacted with the moleculesand/or of a byproduct of reaction of the functionalized ionic liquidwith the chemical or biological compound, and the extract includes amixture of the extraction fluid and of excess of the unreacted compoundand/or of the reaction byproduct, the raffinate including the molecules.54. The process as claimed in claim 35, wherein the microdrop subjectedto the extraction comprises molecules of the chemical or biologicalcompound supported by the functionalized ionic liquid, and the extractcomprises, by cleavage of the support, a mixture of the extraction fluidand of the compounds separated from the functionalized ionic liquid, theraffinate comprising the latter.
 55. The process as claimed in claim 35,wherein the at least one of the functionalized ionic liquids is chosenfrom the group consisting of an ammonium salt, an imidazolium salt, aphosphonium salt, an onium salt, and a mixture of plural of these salts.56. The process as claimed in claim 35, wherein the extraction fluidincludes at least one volatile organic solvent chosen from the groupconsisting of diethyl ether, ethyl acetate and chlorinated solvents,dichloromethane, chloroform or carbon tetrachloride.
 57. The process asclaimed in claim 35, wherein the extraction fluid includes at least oneaqueous solvent or water subjected to deionization.
 58. A microfluidicsystem for implementation of a process as claimed in claim 35,exhibiting a substrate, one surface of which is covered with electrodesconfigured to move thereon, under effect of an electric field,microdrops of a liquid phase including at least one functionalized ionicliquid, the system comprising: means for introducing a liquid extractionfluid onto the surface and for the liquid extraction fluid extractingfrom the orifice by forced convection, to obtain an extraction bathlocated on the surface for extraction of the at least one chemical orbiological compound from the liquid phase and that is open to asurrounding space on at least two of its opposite sides, for moving, incontact with the surface, the microdrop upstream and downstream of thebath.
 59. The system as claimed in claim 58, wherein the means forintroducing and extracting the extraction fluid are configured for theextraction bath to be formed by a drop of the extraction fluid incommunication with an entire surrounding space situated above thesurface.
 60. The system as claimed in claim 58, further comprising asheet mounted on the surface via vertical supports and that delimits,with the surface, two respectively upper and lower walls defining aconfined volume for the bath, which is in communication substantiallywith an entire lateral surrounding space between the walls.
 61. Thesystem as claimed in claim 58, wherein the means for introducing andextracting the extraction fluid respectively comprises two capillaries,at least one of which extends and emerges above the surface andperpendicular to the surface.
 62. The system as claimed in claim 61,wherein the drop forming the extraction bath is configured to be formedon the surface and under the capillaries extending and emerging abovethe surface.
 63. The system as claimed in claim 61, wherein the at leastone of the capillaries emerges in an orifice of the sheet to be incommunication with the confined volume forming the bath.
 64. The systemclaimed in claim 58, wherein the means for introducing and extractingthe extraction fluid respectively comprises two channels, at least oneof which is embedded in the system and is flush with a surfaceperpendicular to the surface, to be in communication with the bath. 65.The system as claimed in claim 64, wherein the channels are configuredfor the drop forming the bath to cover respective ends of the channels.66. The system as claimed in claim 64, wherein the channels are flushwith the surface between vertical supports that connect the periphery ofthe sheet to the surface, to form the confined volume forming the bath.67. The system as claimed in claim 58, wherein the electrodes arecovered with an electrical insulator.
 68. The system as claimed in claim60, wherein the sheet is based on borosilicate glass or on a plastic andthe vertical supports are based on a photosensitive resin or an epoxyresin, the sheet being deposited on the supports via an adhesive.